Pharmaceutical compositions and their preparation



3,449,489 PHARMACEUTICAL COMPOSITIONS AND THEIR PREPARATION William E. Gaunt, 280 Prospect Ave., Hackensack, NJ. 07601 No Drawing. Filed Oct. 21, 1965, Ser. No. 500,297 Int. Cl. A61k 27/12, 15/00 US. Cl. 424-31 35 Claims ABSTRACT OF THE DISCLOSURE Small cuboidal dosage forms of a variety of medicaments are provided which can be either sustained release or enteric in nature. The biologically active agent is dissolved in a volatile solvent or solvent mixture with a film former or film forming polymer and the solution is cast onto a fiat surface, the solvents evaporated and the remaining flexible film cut into strips and then transversely to form the cuboidal particles which are clear, transparent and glass-like in appearance.

The present invention relates to new and unique dosage forms of pharmaceutical compositions which are characterized by being either sustained release dosage forms or enteric dosage forms as well as to the production of such compositions. In co-epnding application Ser. No. 283,623, filed May 27, 1963, now Patent No. 3,328,256, issued June 27, 1967, spheroidal dosage forms of medicaments have been described and claimed wherein the spheroidal particles are produced in uniform size by permitting discrete drops of a suitable volatile solvent to fall on a powder bed of minute particles of appropriate solid materials. According to that application the medicament is introduced into the spheroidal bodies or particles by dissolving them in the solvent or solvent system or by incorporating the same into the powder bed of solid materials.

The present invention relates to cuboidal or other shaped particles or bodies and their production while using the same types of materials employed in making the spheroidal bodies or particles mentioned above.

By the present process a selected biologically active material is dissolved in a suitable volatile solvent or mixture of volatile solvents together with a film former or film forming polymer or a mixture of film formers or film forming polymers, casting the co-solutions on to a flat surface such as a shallow pan to produce a film, evaporating the bulk of the solvent at a slow rate to prevent the formation of bubbles or other discontinuities in the film, removing the flexible film from the flat surface, cutting the film into strips of a width equal to the thickness of the film as by means of cutting blades of razor sharpness, cutting the resulting strips as by means of said cutting blades of razor sharpness into lengths substantially equal to the width of the strips and the thickness of the film thereby to form small cubes. The solvent which is otherwise tenaciously held is removed from the cubes by heating at a temperature of 60 C. in an oven for several hours or days and at the end of the procedure there are formed small cuboidal substantially identical particles of a high degree of hardness and integrity and of an unexpectedly pleasing appearance since the cuboidal particles or bodies are clear, transparent and glass-like with the sparkling refiectivity of jewels.

The clarity, transparency and glass-like appearance were quite unexpected and surprising since for the most part the biologically active materials used are crystalline chemicals readily dissolving in the solvent or solvent mixtures used and readily becoming crystalline again on removal of the solvent or solvent mixtures by evaporation. It would have been thought that upon evaporation of the nite States Patent ice solvent or solvent mixtures from the co-solution of medicament and film former, the medicament would crystallize out within the film to provide an opaque, heterogeneous structure. Surprisingly, however, this did not occur and the medicament remained homogeneous within the film former during the evaporation of the solvent and became a solid solution within the film after the complete disappearance of all residual traces of the volatile solvent. Clear, glass-like films and cuboidal particles or bodies have been made containing as much as 50% of a crystalline medicament free from any signs of crystallization occurring in the solid solution even after several months of observation. Films and cuboidal particles or bodies can, however, be made containing up to 70% more or less of the crystalline medicament but it is generally preferred not to exceed about 50% since the higher proportions above 50% do show some signs of crystallization, particularly on the surface of the film.

Solid solutions of the nature described above have been produced with a wide variety of biologically active materials in a wide variety of film formers or mixtures of film formers. It has further been found that such solid solutions are for the most part characterized by the Water solubility of the film formers used and not by the water solubility of the biologically active materials. For example, when the film former is water insoluble, the solid solution of medicament in the film former is likewise water insoluble even though the medicament itself is highly water soluble and only a very small portion of the medicament in the solid solution dissolves in the Water, the remainder staying indefinitely within the film forming substance. When the film former is insoluble in acid but soluble in alkali, the solid solution of medicament in the film former is insoluble in acid and soluble in alkali; similarly, when the film former is soluble in acid and insoluble in alkali, the solid solution of the medicament in the film former is soluble in acid and insoluble in alkali so that the inherent solubility characteristics of the medicament have very little influence on the outcome, thereby making it possible to use any desired medicament or combination of medicaments irrespective of the solubility characteristics thereof. When a compatible mixture of film formers of difiering water solubility characteristics is used, the solid solution of the medicament or compatible mixture of medicaments possesses water solubility characteristics which are a compromise of those solubility characteristics possessed by the different film formers present in the mix.

The following film formers and film forming polymers have been used singly and in combination in making cuboidal particles or bodies of biologically active substances in solid solution, it being understood that the list below is intended only as illustrative and not as limitative:

cellulose acetate cellulose acetate propionate cellulose acetate butyrate cellulose acetate p'hthalate cellulose acetate succinate cellulose acetate diethylamino'acetate polyvinyl pyrrolidone polyvinyl acetate phthalate copolymer shellac sandarac methyl cellulose hydroxypropyl cellulose aluminum abietate aluminum octoate aluminum laurate aluminum naphthenate aluminum acetyl salicylate aluminum acetate sodium cellulose acetate phthalate.

The following solvents have been used singly and in combination, it being understood that they are given by way of example only:

methanol ethanol isopropanol acetone methylene chloride chloroform ethylene dichloride dimethylsultfoxide water.

Biologically active substances used in carrying out the present invention include without limitation thereto materials having activity of the following types:

anorexic drugs anticholinergic antispasmodics antihistamines antihelmintics choline esterase inhibitors tranquilizers barbiturate sedatives corticosteroids and other steroids anti-infective agents decongestants cardiovascular agents sympathomimetics parasympatholytic agents.

It has further been found that not only crystalline chemicals or drugs can be incorporated into the solid solutions in the film former according to the invention, but also solvent soluble liquids, oils and waxy materials can be similarly incorporated to produce solid cuboidal particles or bodies containing up to 60% of the liquid, oily or waxy materials with no outward visible sign or appearance of the liquid, oily or waxy materials which have been incorporated in the film formers. For example, castor oil, phendimetrazine base, dioctyl sodium sulfosuccinate, and polyoxyethylene sorbitan mono-oleate have been transformed into solid solutions in the film formers.

' It is to be understood that the size of the cubes or cuboidal particles or bodies can be considerably varied and controlled by the thickness of the film cast on to the flat surface and such control is readily effected by varying the relationship between the solid or non-volatile content of the solvent solution and the area of the fiat surface, e.g. of the shallow dish or pan into which the solution is poured. The following table shows the relationship of dry film thickness to solids content per cm. of surface area:

TABLE Dry film thickness, inches: Solids per cm. Area, mg. 0.02 65 The flexibility, elasticity and handling characteristics of the films can be beneficially influenced by the incorporation of an acceptable plasticizer into the solid solution of biologically active material in the film former. Phthalate esters such as dimethylphthalate and diethylphthalate can be used as well as other plasticizers such as acetyltributyl citrate and acetyltriethyl citrate both of which have been found to be useful in amounts ranging from about 10 to 25% of the weight of the film. This percentage range is preferred but is not intended in a limitative sense. In addition to improving the handling properties of the film, the plasticizers impart greater toughness and elasticity to the cuboidal particles or bodies than they would otherwise normally possess.

The present invention takes advantage of this phenom-- enon of soild solution of biologically active materials in film formers in the preparation of specified dosage forms, namely, sustained release dosage forms and dosage forms behaving like enterically coated products but possessing a much higher degree of reliability than conventional enteric coated tablets. By the suitable selection of the mixture and proportions of film forming materials, the rate of solubilization of the cuboidal particles or bodies is simulated alimentary fluids can be controlled with a high degree of accuracy and to provide any desired release pattern.

Examples are set forth below which are intended primarily as illustrative of the various features and characteristics into which the cubes can be designed. Certain examples show that when the film former is, for example, predominantly cellulose acetate phthalate, the cubes resist exposure to an acid environment but readily respond on exposure to an alkaline environment. In contrast an example has been given showing that with suitable proportions of cellulose acetate phthalate and aluminum acetyl salicylate as the co-film formers, the cubes are essentially independent of pH, dissolving and releasing the medicament content at essentially the same rate over a pH range from 1 to 8. This is especially advantageous in sustained release dosage form of medicaments since with such cubes drug release is practically directly a function of time and not a function of the location of the cubes in the alimentary tract. Under these circumstances, drug release is continuous from the moment of ingestion to the complete dissolution of the cubes and the rate of this continuous release can be controlled. Other exam ples provide data demonstrating that the composition of the cubes remains essentially the same during the course of their going into solution and that solubility characteristics of the drugs themselves have no major influence on the release rates. Still other examples show that shellac or polyvinylacetate phthalate copolymer produces cubes dissolving more slowly than those obtained when using cellulose acetate phthalate.

It will also be appreciated that it is within the scope of this invention for one or more film formers and the biologically active material or materials to be added to a solvent and an additional film former to be added to a separate quantity of solvent. The two solutions may then be mixed to produce at least one biologically active substance in solution with a plurality of film formers.

It is further to be understood that the films or copolymer films need not necessarily be cut into cubes as they can optionally or as desired be cut into other shapes such as rectangular, diamond-shapes and cylindrical shapes while still possessing the same desirable solubility characteristics.

Products produced in accordance with the invention have several advantageous features. Each cuboidal or other shaped particle or body has a homogeneous structure and each one releases identically or substantially identically like every other one and there is no mix of different release rates since the shaped particles or bodies can all be made of uniform, predetermined size. Since each shaped particle or body is homogeneously stable and is uncoated, there is no coating to crack or disintegrate. The process for producing the particles or bodies is unusually simple and direct the release rate is controlled by the weight of the ingredients. The particles or bodies are reproducible from batch to batch without any material or appreciable variation from one to another. The particles or bodies can be so produced that they are essentially independent of pH but whenever desired they Example 1 10 grams of cellulose acetate phthalate were suspended in 100 ml. of water and transformed into the water soluble sodium salt by the slow addition of dilute NaOH solution.

200 mg. of Vitamin B were added to the above solution which was stirred until the B was dissolved. 2 grams of dibasic aluminum acetate was dissolved in water, added with stirring to the solution of B and sodium cellulose acetate phthalate. The mixed solutions were poured into a fiat surface and the water permitted to evaporate. The partially dried clear, pink film was cut into cubes and the cubes further dried by heating to 60 C.

The hard, dry, clear cubes resisted exposure to simulated gastric fluids but readily dissolved in simulated intestinal fluids.

Example 2 10 grams of pentapiperide methyl sulfate and 10 grams of polyvinylacetate phthalate copolymer were dissolved in 50 ml. of a mixture of 80 parts methylene chloride and 20 parts methanol, 20 grams of aluminum acetyl salicylate were dissolved in 50 ml. of this same solvent mix. The two solutions were mixed and poured into a shallow tray of approximately 250 cm. area. The solvent was permitted to evaporate slowly and when the film Weighed about 50 grams, it was removed from the dish and cut into cubes approximately 0.05 in dimension. The remaining solvent was removed in the oven at 60 C.

On testing the release characteristics of these cubes, using the rotating bottle technique of Souder and Ellenbogen published in Drug Standards, volume 26 (1958) page 77, the following data were obtained:

Percent cumulative release 1 hour gastric 18.5 1 hour gastric plus 1 hour intestinal 25.0 1 hour gastric plus 3 hours intestinal 35.0 1 hour gastric plus 7 hours intestinal 45.5

Pentapiperide methyl sulfate, parts. 9 9

Cellulose acetate phthalate, parts 12 6 Polyvinylacetate phthalate co-polymer,

parts 6 Aluminum acetyl salicylate, parts 24 24 When tested by the procedure described the release characteristics of the two samples were as follows:

Percent Cumulative Release 1 hour gastric 25.0 17. 1 hour gastric plus 1 hour intestinal 57. 5 42. 5 1 hour gastric plus 3 hours intestine 87. 5 67. 5 1 hour gastric plus 7 hours intestinal" 97. 5 90. 0

Example 3 grams of phendimetrazine hydrochloride, 10 grams of wax free white shellac and 3 grams of diethyl phthalate were dissolved in 60 ml. of a solvent composed of 80 parts chloroform and parts methanol. 20 grams of aluminum acetyl salicylate were dissolved in the same solvent. The two solutions were mixed and poured into a fiat dish of approximately 300 cm. area. The solvent was allowed to evaporate slowly and when the film weighed about 55 grams, it was removed from the dish and cut into cubes. The remaining solvent was removed in the oven at 60 C.

These cubes had the following release characteristics:

Percent cumulative release 1 hour gastric 24 1 hour gastric plus 1 hour intestinal 42 1 hour gastric plus 3 hours intestinal 66 1 hour gastric plus 7 hours intestinal 82 Example 4 2.5 grams of valethamate bromide, 2.5 grams of refined gum sandarac and 1 gram of acetyl tributyl citrate were dissolved in 20 ml. of a mixture of parts methylene chloride and 20 parts methanol. 5 grams of aluminum acetyl salicylate were dissolved in 20 ml. of the same solvent mixture. The two solutions were mixed and poured into a fiat dish of about 70 cm. area. The solvent was slowly permitted to evaporate and the resultant flexible film cut into cubes. The remaining solvent was removed in the oven at 60 C.

The release characteristics of these cubes were as follows:

Percent cumulative release 1 hour gastric 28 1 hour gastric plus 1 hour intestinal 47 1 hour gastric plus 3 hours intestinal 71 1 hour gastric plus 7 hours intestinal 88 Example 5 1.5 grams of isothipendyl hydrochloride, 0.5 gram of diethyl phthalate and 2.67 grams of cellulose acetate phthalate were dissolved in 20 ml. of a solvent mix of 80 parts methylene chloride and 20 parts methanol. 5.34 grams of aluminum abietate were dissolved in the same solvent mix. The two solutions were mixed and then poured into a fiat dish of approximately 70 cm. area. After most of the solvent had evaporated, the film was removed from the dish and cut into cubes. The remaining solvent was removed by heating in the oven at 60 C.

These cubes had the following release characteristics:

Percent cumulative release 1 hour gastric 26 1 hour gastric plus 1 hour intestinal 51 1 hour gastric plus 3 hours intestinal 74 1 hour gastric plus 7 hours intestinal 92 Example 6 4 grams of chlorpheniramine maleate, 6 grams of polyvinyl pyrrolidone and 10 grams of cellulose acetate phthalate were dissolved in 90 ml. of a solvent mix consisting of 70 parts methylene chloride and 30 parts methanol. 20 grams of aluminum acetyl salicylate were dissolved in 70 ml. of the same solvent composition. The two solutions were mixed and poured into a shallow flat dish of approximately 350 cm. area. The solvent was permitted to evaporate and the film removed from the dish and cut into cubes. The remaining solvent was removed in the oven at 60 C.

Example 7 Two samples of cubes of the following composition were made:

The release characteristics of these samples were as follows:

Percent Cumulative Example 8 6.75 grams of pentapiperide methyl sulfate and 7.65 grams of cellulose acetate phthalate were dissolved in 50 ml. of a mixture of 70 parts methylene chloride and 30 parts methanol. 30.6 grams of aluminum acetyl salicylate were dissolved in 75 ml. of the same solvent mixture. The latter solution was added to the former and the whole mixed and poured into a flat dish of approximately 300 cm. area. The solvent was allowed to evaporate slowly until the weight of the film was approximately 55 grams. The clear, flexible film was removed from the tray and cut into cubes of about 0.06" dimension. The remaining solvent in the cubes was removed in the oven at 60 C.

This sample gave the following release data on exposure to simulated alimentary fluids:

Percent cumulative release 1 hour gastric 37 1 hour gastric plus 1 hour intestinal 57 1 hour gastric plus 3 hours intestinal 78 1 hour gastric plus 7 hours intestinal 95 The release characteristics of these cubes were also determined on continuous exposure to simulated gastric fluids at pH 1.1 and to simulate intestinal fluids adjusted to pH 4.5, pH 6.7 and pH 7.7.

Percent Cumulative Release pH 1.1 pH 4.5 pH 6.7 pH 7.7

1 hour 38 21 21 22 2 hours 48 34 40 42 4 hours 64 42 63 70 Example 9 20 ml. of castor oil, 8 grams of cellulose acetate succinate and 3 grams of diethyl phthalate were dissolved in 80 ml. of a solvent mixture composed of 70 parts methylene chloride and 30 parts methanol. 2 grams of dibasic aluminum acetate were dissolved in 20 ml. of the same solvent. The two solutions were mixed and poured into a flat stainless steel tray with a surface area of approximately 200 cm. The solvent was slowly allowed to evaporate and the flexible film obtained was removed from the tray and cut into cubes. The remaining solvent was removed by heating in the oven at 60 C. The dry cubes were firm and tough, giving no indication that they were 60 percent composed of oil.

Example 10 5 grams chlordiazepoxide, 5 grams of cellulose acetate phthalate and 3 grams of acetyl tributyl citrate were dissolved in 40 ml. of a mixture of 7 parts methylene chloride and 3 parts isopropanol. grams of aluminum acetyl salicylate were dissolved in 60 ml. of the same solvent mix. The two solutions were mixed, poured into a shallow stainless steel tray having a surface area of 200 cm. The solvent was permitted to evaporate slowly and when the weight of the film was about 40 grams,

it was removed from the tray and cut into cubes. The remaining solvent was removed at 37 C.

Example 11 1 gram of iodine was dissolved in ml. of a solvent composed of 7 parts methylene chloride and 3 parts methanol. In this solution were then dissolved 10 grams of polyvinyl pyrrolidone and 20 grams of cellulose acetate phthalate. 2 grams of dibasic aluminum acetate were dissolved in 20 ml. of the same solvent mix and added with stirring to the above solution, the mixture then being cast into a flat dish. After the evaporation of most of the solvent, the film was cut into cubes and the remaining solvent was permitted to evaporate at room temperature. The dried cubes resisted the attacks of simulated gastric fluids but readily dissolved on exposure to simulated intestinal fluids.

Example 12 170 grams of 0,0-dimethyl 2,2,2-trichloro-hydroxyethyl phosphonate, 30 grams of diethyl phthalate and grams of cellulose acetate phthalate was dissolved in 800 ml. of a solvent mix composed of 9 parts methylene chloride and 1 part methanol. 10 grams of aluminum octoate was suspended in 50 ml. of methanol and added to the above solution with mixing. The mixture was poured into a flat aluminum dish of 2,000 cm. area and the solvent allowed to evaporate slowly. When the film weighted 400 grams, it was removed from the tray and cut into cubes. The remaining solvent was removed by heating in the oven at 50 C.

On exposure to simulated gastric fluid for 1 hour, the cubes released less than 10 percent of their content of 0,0- dimethyl 2,2,Z-trichloro-hydroxycthyl phosphonate, but on exposure thereafter to simulated intestinal fluids complete release of the phosphonate compound occurred in less than 30 minutes. It is apparent that when the film formers are used in these proportions, the cubes obtained possess essentially enteric-coated solubility characteristics and not the sustained-release characteristics obtained when the proportion of the film formers are more nearly equal.

Example 13 20 grams of hexylresorcinol, 7 grams of cellulose acetate phthalate and 3 grams of acetyl tributyl citrate were dissolved in 60 ml. of a mixture of 9 parts chloroform and 1 part ethanol. 1 gram of aluminum laurate was suspended in 10 ml. ethanol and added to the above solution with stirring. The mix was poured into a flat dish of about 200 cm. area and the solvent allowed to evaporate.

The flexible film was cut into cubes and the remaining solvent removed by heating in the oven at 60 C.

The resultant cubes resisted exposure to simulated gastric fluids but dissolved quite rapidly in simulated intestinal fluids.

Example 14 2.5 grams of pentapiperide methyl sulfate and 10 grams of cellulose acetate propionate were dissolved in 75 ml. of a mixture of chloroform-80%, ethylalcohol- 20%. The clear solution was poured into a fiat glass dish of 70 cm. area and the solvent permitted to evaporate slowly. After most of the solvent had disappeared, the flexible film was removed from the dish and cut into strips as wide as the film was thick (approximately .070") and the strips then cut into cubes. The remaining solvent was removed by placing the cubes in an oven at 60 C.

On exposure to simulated gastric fluids at 37 C., the cubes lost 10% of their weight and 15% of the pentapiperide methyl sulfate. On exposure thereafter to simulate intestinal fluids for 4 hours, there was no further loss in weight and no further loss in pentapiperide methyl sulfate and the cubes remained glass-clear throughout this exposure to the aqueous environment.

9 Example 15 7 grams of pentapiperide methyl sulfate, 7 grams of cellulose acetate phthalate, 7 grams of cellulose acetate diethylamino acetate and 4 grams of diethyl phthalate were dissolved in 100 ml. of an 8020 mixture of chloroform and ethanol. 21 grams of aluminum acetyl salicylate were dissolved in 75 ml. of the same solvent mixture and added to the same solution. The whole was stirred and then cast into a flat dish of approximately 300 cm. area and the solvent permitted slowly to evaporate. When the total weight of the film had fallen to 60 grams (25% solvent content), it was removed from the dish and cut into cubes about .075 in dimension. The remaining solvent was removed by heating in the oven at 60 C. overnight.

sulfate. The pentapiperide methyl sulfate contents of the exposed samples are given below:

Percent pentapiperide methyl sulfate After 1 hour gastric 22.3 After 1 hour gastric plus 1 hour intestinal 22.7 After 1 hour gastric plus 3 hours intestinal 20.3

Curnu- Pentapiperide Cumula- Wt. of lative methyl sulfate tive sample percent content of Percent; (mg) wt. loss sample (mg) drug release Initial sample 400 100 1 hour gastric 290 27. 64. 5 35. 5 1 hour gastric plus 1 hour intestinaL 200 50.0 45. 5 54. 4 1 hour gastric plus 3 hours intestinal- 95 76. 5 19. 5 80. 5

Example 16 Example 18 2.5 grams of pentapiperide methyl sulfate, 5 grams of cellulose acetate phthalate and 5 grams of cellulose acetate diethyl amino acetate were dissolved in a mixture of 40 ml. of chloroform and ml. of methanol. The solution was cast into a flat dish of about 75 cm. area and the solvent permitted slowly to evaporate. The flexible film was then cut into cubes and the remaining solvent removed by heating in the oven at 60 C.

On exposure to simulated gastric fluids for one hour and simulated intestinal fluids thereafter at 37 C. in the rotating bottle equipment, the following data were obtained:

Percent cumulative release 1 hour gastric 20 1 hour intestinal 28 3 hours intestinal 7 hours intestinal 65 Example 17 13 grams of pentapiperide methyl sulfate and 13 grams of cellulose acetate phthalate were dissolved in a mixture of 80 ml. methylene chloride and 20 ml. methanol. 26 grams of aluminum acetyl salicylate were dissolved in 70 ml. of the same solvent mixture, this solution being added to the above solution. The whole was mixed and poured into a shallow tray of approximately 300 cm. area. The solvent was permitted to evaporate slowly and when the weight of the film was about 70 grams, it was removed from the tray and cut into cubes approximately 0.07" in dimension. The remaining solvent was removed in an oven at 60 C. overnight.

400 mg. samples of these cubes were exposed to simulated gastric fluids and thereafter to simulated intestinal fluids at 37 C. in the rotating bottle equipment.

One sample was removed after the exposure to simulated gastric fluids and dried at 60 C. to constant weight. Sim ilarly, a sample was removed after the one hour treatment with simulated gastric fluids followed by one hour exposure to simulated intestinal fluids and dried to constant weight at 60 C. A third sample was removed after an additional 2 hours of exposure to simulated intestinal fluids )1 hour gastric plus 3 hour intestinal) and dried to constant weight. The dried samples were then assayed for their pentapiperide methyl sulfate content.

The original cubes were made to contain and were found by assay to contain 25.0% of pentapiperide methyl The following example was designed to illustrate that the rate of dissolution of the film formers in the cube compositions is the dominant factor in the release of drugs from the cubes and that the solubility characteristics of the drugs themselves are quite subordinate factors.

Cubes of the following compositions were made:

Parts Pentapiperide methyl sulfate 1.5 Chlorpheniramine maleate 1.5 Phenobarbital 1.5 Hydrocartisone 1.5 Cellulose acetate phthalate 4.5 Diethyl phthalate 3.0 Aluminum acetyl salicylate 18.0

The drugs used in this preparation were selected for their widely varying solubility characteristics as indicated below:

to simulated gastric fluids for 1 hour followed by simulated intestinal fluids for a further period of 1 hour. The residual cube substances remaining after this exposure were dried to constant weight and then assayed for their drug content.

The cubes lost 26 percent of their substance during the 1 hour exposure to simulated gastric fluids and lost 45% of their substance after exposure for 1 hour to simulated gastric fluids followed by 1 hour of exposure to simulated intestinal fluids. By assay it was found that despite these weight losses, the composition of the preparation in terms of its content of the various drugs remained essentially constant, the data reflecting no substantial difference in the release of the different drugs as a consequence of their differing solubility characteristics.

Percent Drug Content of the Cubes Initial After 1 hr. gastric plus Found by After 1 hr. 1 hr. inlheory assay gastric testinal Pentapiperide methyl sulfate 4. 75 4. 7 4. 6 4. 3 Chlorpheniramine maleate 4. 75 4. 6 4. 2 4. 3 Phenobarbital 4. 75 4. 7 4. 4. 2 Hydrocortisone 4. 75 4. 5 4. 4 4. 1

The rate of release of the different drugs from the cubes during the exposure to which they were subjected is given below:

What is claimed is:

1. A process of making a shaped pharmaceutical oral dosage unit product having essentially enteric or sustained release solubility characteristics in simulated gastric and intestinal fluids in which a predetermined rate of solubilization of the product is obtained independent of the inherent solubility characteristics of the medicament solely by correlation to the acid-insolubility and alkalisolubility and amount of a pre-selected film former in the form of hard, clear, glass-like cuboidal particles with the sparkling reflectivity of jewels which comprises preparing a solution of up to 50% of at least one biologically active crystalline, oily, waxy, semi-solid or liquid medicament substance and at least one film former in a volatile solvent, casting the solution on a fiat surface to form a film, evaporating a major proportion of the solvent at a slow rate to prevent the formation of bubbles or other discontinuities in the film, removing the film from the flat surface, cutting the film into cuboidal particles from about 0.05 inch to about 0.075 inch in dimension each being a predetermined portion of an orally effective dosage unit quantity of medicament and evaporating the remaining solvent, which is otherwise tenaciously held, by heating at a temperature of 60 C. until the at least one biologically active medicament substance is formed in solid, clear, transparent and glass-like solution in the small cuboidal substantially identical particles with a high degree of hardness and integrity and with the sparkling reflectivity of jewels, the at least one film former being selected from the group consisting of cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate diethylaminoacetate, polyvinyl acetate phthalate co-polymer, shellac, sandarac, aluminum abietate, aluminum octoate, aluminum laurate, aluminum naphthenate, aluminum acetyl salicylate, aluminum acetate, sodium cellulose acetate phthalate, mixtures thereof, and mixtures of any of the foregoing film formers with polyvinyl pyrrolidone, methyl cellulose or hydroxypropyl cellulose.

2. A process according to claim 1 in which the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, chloroform, methylene chloride, ethylene and dichloride and mixtures thereof.

3. A process according to claim 1 in which the at least one biologically active substance is selected from the group consisting of antihistamines, antihelmintics, choline esterase inhibitors, tranquilizers, barbiturate sedatives, corticosteroids and other steroids, anti-infective agents, decongestants, cardiovascular agents, sympathomimetics, parasympatholytic agents, and combinations thereof.

4. A process according to claim 1 in which the at least one biologically active substance is Vitamin B the solvent is water and the at least one film former is sodium cellulose acetate phthalate.

5. A process according to claim 1 in which the at least one biologically active substance is pentapiperide methyl sulfate, the solvent is a mixture of methylene chloride and methanol and the at least one film former is polyvinyl acetate phthalate copolymer and aluminum acetyl salicylate.

6. A process according to claim 1 in which the at least one biologically active substance is phendimetrazine hydrochloride, the solvent is a mixture of chloroform and methanol and the at least one film former is shellac and aluminum acetyl salicylate.

7. A process according to claim 1 in which at least one biologically active substance is valethamate bromide, the solvent is a mixture of methylene chloride and methanol and the at least one film former is gum sandarac and aluminum acetyl salicylate.

8. A process according to claim 1 in which the at least one biologically active substance is isothipendyl hydrochloride, the solvent is a mixture of methylene chloride and methanol and the at least one film former is cellulose acetate phthalate.

9. A process according to claim 1 in which the at least one biologically active substance is chlorpheniraamine maleate, the solvent is a mixture of methylene chloride and methanol and the at least one film former is a mixture of polyvinyl pyrrolidone and cellulose acetate phthalate, and aluminum acetyl salicylate.

10. A process according to claim 1 in which the at least one biologically active substance is pentapiperide methyl sulfate, the solvent is a mixture of methylene chloride and methanol and the at least one film former is cellulose acetate phthalate and aluminum acetyl salicylate.

11. A process according to claim 1 in which the at least one biologically active substance is castor oil, the solvent is a mixture of methylene chloride and methanol and the at least one film former is cellulose acetate succinate.

12. A process according to claim 1 in which the at least one biologically active substance is chlordiazepoxide, the solvent is a mixture of methylene chloride and isopropanol and the at least one film former is cellulose acetate phthalate.

13. A process according to claim 1 in which the at least one biologically active substance is iodine, the solvent is a mixture of methylene chloride and methanol and the at least one film former is a mixture of polyvinyl pyrrolidone and cellulose acetate phthalate.

14. A process according to claim 1 in which the at least one biologically active substance is 0,0-dimethy1 2,2,2-trichlorohydroxyethyl phosphonate, the solvent is a mixture of methylene chloride and methanol and the at least one film former is a mixture of cellulose acetate phthalate and aluminum octoate.

15. A process according to claim 1 in which the at least one biologically active substance is hexylresorcinol, the solvent is a mixture of chloroform and ethanol and the at least one film former is a mixture of cellulose acetate phthalate and aluminum laurate.

16. A process according to claim 1 in which the at least one biologically active substance is pentapiperide 13 methyl sulfate, the solvent is a mixture of chloroform and ethyl alcohol and the at least one film former is cellulose acetate propionate.

17. A process according to claim 1 in which the at least one biologically active substance is pentapiperide methyl sulfate, the solvent is a mixture of chloroform and ethyl alcohol and the at least one film former is a mixture of cellulose acetate phthalate and cellulose acetate diethylamino acetate.

18. A process according to claim 1 in which the at least one biologically active substance is pentapiperide methyl sulfate, the solvent is a mixture of chloroform and methanol and the at least one film former is a mixture of cellulose acetate phthalate and cellulose acetate diethylamino acetate.

19. A process according to claim 1 in which the at least one biologically active substance is pentapiperide methyl sulfate, the solvent is a mixture of methylene chloride and methanol and the at least one film former is a mixture of cellulose acetate phthalate and aluminum acetyl salicylate.

20. A shaped pharmaceutical oral dosage unit product having essentially enteric or sustained release solubility characteristics in simulated gastric and intestinal fluids in which a predetermined rate of solubilization of the product is obtained independent of the inherent solubility characteristics of the medicament solely by correlation to the acid-insolubility and alkali-solubility and amount of a preselected film former in the form of hard, clear, glass-like cuboidal particles with the sparkling reflectivity of jewels consisting essentially of a homogeneous solution of up to 50% of a predetermined portion of an orally effective dosage unit quantity of at least one biologically active crystalline, oily, waxy, semi-solid or liquid medicament substance in at least one film former, the at least one film former being selected from the group consisting of cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate sucoinate, cellulose acetate diethylaminoacetate, polyvinyl acetate phthalate co-polymer, shellac, sandarac, aluminum abietate, aluminum octoate, aluminum laurate, aluminum naphthenate, aluminum acetyl salicylate, aluminum acetate, sodium cellulose acetate phthalate, mixtures thereof, and mixtures of any of the foregoing film formers with polyvinyl pyrrolidone, methyl cellulose or hydroxypropyl cellulose, said cuboidal particles being from 0.05 inch to about 0.075 inch in dimension prepared in accordance with the process of claim 1.

21. A shaped pharmaceutical product according to claim 20, in which the at least one biologically active substance is solid and crystalline.

22. A shaped pharmaceutical product according to claim 20, in which the at least one biologically active substance is liquid, oily or waxy.

23. A shaped pharmaceutical product according to claim 20, in which a plasticizer is incorporated into the at least one film former.

24. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of Vitamin B in the at least one film former.

25. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentiallyof a solid solution of pentapiperide methyl sulfate in the at least one film former.

26. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of phendimetrazine hydrochloride in the at least one film former.

27. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of valethamate bromide in the at least one film former.

28. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of isothipendyl hydrochloride in the least one film former.

29. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of chlorpheniramine maleate in the at least one film former.

30. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of methamphetamine in the at least one film former,

31. Dry cuboidal particles according to claim 20 of a solution of castor oil in the at least one film former.

32. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of a solid solution of chlordiazepoxide in the at least one film former.

33. Cuboidal particles according to claim 20 of a solid solution of crystalline iodine in a mixture of polyvinyl pyrrolidone cellulose acetate phthalate and aluminum acetate.

34. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of 0,0-dimethyl 2,2,2- trichloro-hydroxyethyl phosphonate in the at least one film former.

35. Hard, clear, glass-like cuboidal particles according to claim 20 consisting essentially of hexylresorcinol in the at least one film former.

Martin: HUSAs Pharmaceutical Dispensing, (5th ed.), pp. 78-80, Mack Pub. Co., Easton, Pa. (1959) (POSL RS 91H8 1959).

LEWIS GOTTS, Primary Examiner.

S. K. ROSE, Assistant Examiner.

US. Cl. X.R. 

